Methods and benzamide compositions for producing hypotensive activity

ABSTRACT

Hypotensive pharmaceutical compositions comprising effective amounts of compounds of the formula:   WHEREIN A, B, and C are selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, and halogen radicals at least one of which is an alkoxy or a halogen radical; wherein x is a whole number from one to three, and wherein R is selected from the group consisting of cycloaliphatic radicals containing between three and seven carbon atoms, together with carriers therefor, and the methods for administering said compounds.

United States Patent 1 Roll [451 May 20, 1975 METHODS AND BENZAMIDECOMPOSITIONS FOR PRODUCING HYPOTENSIVE ACTIVITY [75] Inventor: WilliamD. Roll, Toledo, Ohio [73] Assignee: The University of Toledo, Toledo,

Ohio

[22] Filed: Apr. 25, 1974 [21] Appl. No.: 463,959

Related US. Application Data [60] Division of Ser. No. 336,415, Feb. 28,1973, Pat. No. 3,808,315, which is a continuation-in-part of Ser. No.180,206, Sept. 13, 1971, abandoned, which is a division of Ser. No.822,029, May 5, 1969, Pat. No.

Primary Examiner-Albert T. Meyers Assistant Examiner-Norman A. Drezin 57] ABSTRACT l-lypotensive pharmaceutical compositions comprisingeffective amounts of compounds of the formula:

(CH CN 7/ R C wherein A, B, and C are selected from the group consistingof hydrogen, lower alkyl, lower alkoxy; and halogen radicals at leastone of which is an alkoxy or a halogen radical; wherein x is a wholenumber from one to three, and wherein R is selected from the groupconsisting of cycloaliphatic radicals containing between three and sevencarbon atoms, together with carriers therefor, and the methods foradministering said compounds.

12' Claims, No Drawings METHODS AND BENZAMIDE COMPOSITIONS FOR PRODUCINGIIYPOTENSIVE ACTIVITY RELATED APPLICATION This application is a divisionof William D. Roll cpending application Ser. No. 336,415 filed Feb. 28,1973 now US. Pat. No. 3,808,315, which is a continuation-in-part ofWilliam D. Roll copending application Ser. No. 180,206 filed Sept. 13,1971 now abandoned, which is a division of his application Ser. No.822,029 filed May 5, 1969, now US. Pat. No. 3,660,461 issued May 2,1972.

BACKGROUND OF THE INVENTlON Although similar N-cyanoalkyl benzamides areknown, no similar ones were found which had the hypotensive effects ofapplicants compounds. For example; the Crobetti et a1 U.S. Pat. No.3,457,294 patented July 22, 1969 is for antibacterial, antifungal andantiprotozal activity, the Pursglove US. Pat. No. 2,927,126 patentedMar. 1, 1960 is for a biocide, and the Saxon US. Pat. No. 3,172,869patented Mar. 9, 1965 is for a plasticizer.

Although similar N-cycloalkyl benzamides are known, they only hadbiocide or CNS depressant effects, and none had hypotensive activity.

SUMMARY OF THE INVENTION This invention comprises pharmaceuticalcompositions containing various benzamides having hypotensive activityand methods of administering these compositions to small animals toproduce these effects.

The compositions of this invention are unit dosage forms, such astablet, capsule, sterile solution, etc., containing a therapeuticallyeffective amount of benzamide having the general formula:

wherein A, B, and C may be mono-, di-, or tri-fluoro-, chloro-, bromo-,iodo-, methoxy-, or ethoxyradicals may comprise a cyanomethyl-, ethyl-,or propylradical, but preferably the cyanoethyl-radical while the Rradical may comprise a tri-, quatra, penta-, hexa-, or

heptacycloaliphatic radical, preferably cyclohexyl 5 radical, whichtogether with the haloor methoxyradicals on the phenyl ring of thebenzamide confers the proper physicochemical properties on thesecompounds which are necessary for maximal activity in the animalstested. Although the N-cyanoethyl-radical is preferred, theN-cyanopropyl-radical also is good, but the N-cyanomethyl is lesseffective, and these N- cyanoalkyl radicals of four or more carbon atomsproduce no significant hypotensive action in any practical dosages.

These benzamides were prepared by the modification of theSchotten-Baumann Reaction according to the following equation:

R-Q-mci N/CHZCHZCN Herein an acyl halide was reacted with an N-(2-cyanoalkyl)- cycloalkylamine in the presence of sodium hydroxide andchloroform at room temperature and agitated until the exothermicreaction was complete. The chloroform layer was then washed with water,dried with anhydrous sodium sulfate and evaporated in vacuum to producea viscous yellow oil which crystallized on standing for a period ofseveral weeks. This crude product was then re-crystallized from aqueousethanol to give the pure new compounds of this invention, which weretested for composition and physical properties. The results of some ofthese tests on the preferred N-cyclohexyl-N-cyanoethyl-methoxyand 50chlorobenzamides are shown in the following Table l:

TABLE 1 Example Phcnyl Ring Yield Melting Ultra Violet InfraredCalculated Analyzed Numbers Substituted by Above Points Data AbsorptionRadical Process In C=O CN C H C H 1 p-CH;,O- 76.8 77-78 282 1679 16302265 71.30 7.74 71.33 1 7.78 2 mCH;,O 75.0 282 2040 1630 2265 71.30 7.7471.77 7.83 3 oCH O 74.5 43-44 282 2611 1630 2265 71.30 7.74 71.45 7.80 4p-C1 79.4 93-94 266 1500 1630 2265 66.08 6.58 66.20 6.50 5 mCl- 75.048-49 266 757 1630 2265 66.08 6.58 66.12 6.63 6 o-Cl 78.4 56-57 266v 3911630 2265 66.08 6.58 66.14 6.60

and may be monoor di-methyl, or ethylradicals, but preferably chloro- 0rmethoxyradicals substituted in the ortho-, meta, and para-positions, butpreferably in the metaor para-positions, of the phenyl ring of thebenzamide. The cyanoalkyl radical of the benzamide The activity of thesebenzamide compounds was tested by dissolving them in propylene glycoland parenterally injecting the resulting solutions into small animalssuch as rats in dosages of 2 and of 4 milligrams per kilogram of weightof the animal injected. The direct TABLE II At Dosage 4mg./kg. in ratsCompound of Relative Hypotensive The pharmaceutical compositions of thisinvention are composed of these benzamides incorporated in a non-toxicliquid or solid pharmaceutical carrier or excipient. Thus, simplepropylene glycol solutions of the active ingredients have been foundsuitable, however, the active ingredients may be incorporated inpharmaceutical carrier forms, such as tables or capsules, which maycontain other non-toxic materials such as fillers or .diluents, namely:lactose or sucrose, and may contain a binding agent such as glucose, gumacacia, gelatin, starch paste, etc. Furthermore, they may containlubricants, such as magnesium stearate, talc, etc., as well as suchdisintegrating agents as corn starch, microcrystalline cellulose, etc.The active ingredients may also be incorporated into injectablesolutions which may contain other non-toxic materials including:solvents, such as propylene glycol, water for injection, etc., andpreservatives, such as benzyl alcohol, etc.

The unit dosage forms are prepared by standard formulation methods suchas by granulating and tableting, by mixing with a carrier and fillinginto hardgelatin capsules; by dissolving or suspending in a suitablesterile parenteral vehicle; or by dissolving in an aqueous vehicle foran oral liquid dosage form.

The unit dosage forms will contain a sufficient amount of activeingredient to provide effective hypotensive activity with correspondingminimal toxic side effects.

A unit dose range of from approximately 10-150 mg. provides hypotensiveactivity with minimal side reactions. Such unit doses are administeredl-4 times daily. For calculating the amounts of active ingredients inthe claimed unit dosage forms, it is often convenient to use milligramsof the active compounds per kilogram of the weight of the animal towhich they are administered, depending on the activity of the activeingredient together with the size and pharmacology of the host animal.In such claimed unit dosages, the active compound will be present inapproximately 0.5 l mg./kg. but preferably 1 mg./kg. amounts.

The following examples are designed to explain the methods ofpreparation and administrationof the compounds of this invention, but itis to be understood that they are not to limit the scope of thisinvention:

EXAMPLE I N-cyclohexyl-N-cyanoethyl-p-methoxybenzamide was prepared byshaking a mixture of 15 of chloroform, 0.01 mole of N-(-2-cyanoethyl)cyclohexylamine, 6O milliliters of 5% sodium hydroxide, and 0.01 mole ofpmethoxy-acyl chloride in a separator at room temperature until theexothermic action was complete. The chloroform layer was washed withwater, dried with anhydrous sodium sulfate, and evaporated in a vacuumto produce a viscous yellow oil which crystallized on standing for aperiod of several weeks. These crude crystals were then re-crystallizedfrom aqueous ethanol to form the pureN-cyclohexyl-N-cyanoethyl-pmethoxy-benzamide sample of this Example.

This sample was then tested according to the Table I above in which thecarbon and hydrogen content or percentages were obtained with a Colemancarbonhydrogen analyzer. The melting point was determined by using aMettler FP-l melting and boiling point apparatus. The infraredabsorption spectra were obtained with Perkin-Elmer Model l37-Bspectrophotometer, and the ultraviolet data were obtained with a Bauschand Lomb Spectronic 600 Spectrophotometer.

This new compound produced a significant hypotensive effect whenadministered orally or intraperitoneally to unanesthetized normotensiverats.

The oral administration of four milligrams per kilogram of this Example1 compound dissolved in propylene glycol resulted in a significantreduction in blood pressure of rats.

EXAMPLE 2 N-cyclohexyl-N-cyanoethyl-m-methoxybenzamide was prepared fromm-methoxy acyl chloride and N-2- (Z-cyanoethyl) cyclohexylamine in thesame manner as that employed in Example I above, except that it waspurified by chromatography on silica gel and eluted with petroleumether. The resulting compound was also tested as described in Example Iabove, and as shown in Tables I and II above, and in a dose of4 mg./kg.produces a significant reduction in blood pressure.

EXAMPLE 3 N-cyclohexyI-N-cyanoethyl-o-methoxybenzamide also was producedin the manner described in Example I above and similarly tested asdescribed therein and as shown in the above Tables I and II, and wasshown to have blood pressure depressor activity in dosages of 4 mg./kg.

EXAMPLE 4 N-cyclohexyl-N-cyanoethyl-p-chlorobenzamide was also producedaccording to the process described in Example 1 above and similarlytested as shown in Tables I and II.

EXAMPLE 5 N cyclohexyl-N-cyanoethyl-m-chlorobenzamide was also producedsimilar to the process described in Example l, and it hadpharmacological effects similar to those for the compound of Example 2as shown in Table 11.

EXAMPLE 6 N-cyclohexyl-N-cyanoethyl-o-chlorobenzamide was producedaccording to the process described for Example 1 and was tested to haveproperties and an activity 5 slightly less than the compound of Example3.

EXAMPLE 7 Tablet Formulation Cum/Tablet Active Ingredient 0.025 Lactose0.150 Sucrose 0.025 Corn Starch 0.015 Stearic Acid 0.003

These ingredients are granulated and compressed by standardpharmaceutical methods.

EXAMPLE 8 Gm./Capsule Capsule Formulation Active lngredicnt 0.025Magnesium Stearate 0.002 Lactrose, qs ad 0.300

These ingredients are screened, mixed and filled into hard gelatinecapsules.

EXAMPLE 9 Parenteral Formulation Active Ingredient 0.040 o/o Propyleneglycol 60.00 o/o Benzyl alcohol 2.00 olo Water for injection, USP, qsad. 100.00 o/o 6 tive quantity of a compound of the formula:

Q B (ll: N (CH CN wherein A, B and C are selected from the groupconsisting of hydrogen, lower alkyl, lower alkoxy, and halogen, at leastone of which is alkoxy or halogen, wherein x is a whole number from oneto three, and wherein R is cyclo-alkyl containing between three andseven carbon atoms.

2. A method according to claim 1 wherein A is hydrogen and B and C arelocated in the meta-, and parapositions.

3. A method according to claim 1 wherein x is 2.

4. A method according to claim 1 wherein R is cyclohexyl.

5. A method according to claim 1 wherein A is halogen and B and C arehydrogen.

6. A method according to claim 1 wherein A is methoxy and B and C arehydrogen.

7. A method according to claim 1 wherein said compound isN-cyclohexyl-N-cyanoethyl-pmethoxybenzamide.

8. A method according to claim 1 wherein said compound isN-cyclohexyl-N-cyanoethyl-mmethoxybenzamide.

9. A method according to claim 1 wherein said compound isN-cyclohexyl-N-cyanoethyl-pchlorobenzamide.

10. A method according to claim 1 wherein the quality of said compoundadministered is between about 0.5 and 10 milligrams per kilogram of thehost animal.

11. A method according to claim 1 wherein the quantity of said compoundadministered is between about 1 and 5 milligram per kilogram of the hostanimal.

12. A method according to claim 1 wherein said compound together with apharmaceutically acceptable carrier is administered in a unit dosecomposition in the form of a capsule, tablet, or parenteral formulation.

UNITED STATES PA'iiiNl OFFICE CERTIFICATE OF CORRECTION PAT limo.3,885,040

DATED May 20, 1975 INVEM'ORiS William D. ROLL li is certified thai errorappeais in the above-Identified patent and that sa d Leiers Patent 81'8hereby connected as shown below Col. 2, line 11, 1 change these" tothose line 43, after "in" insert a line 56, Table I, 4th column after"In" insert 5th column cancel C1 C01. 3, line 33 change tables" totablets e Col. 4, line 6, after "15" insert milliliters line 25, after"with" insert a Col. 5, line 27, change "Lactrose to Lactose Col. 6,lines 37 & change "quality" to quantity gigncd and Sealed thistwenty-third D fly Of September 1975 [SEAL] Arrest:

RUTH C. MASON C. MARSHALL DANN Arrmring Officer (mnmissimzvr nj'lurenlxum! Truilcmurkx l

1. A METHOD OF PRODUCING HYPOTENSIVE ACTIVITY IN AN ANIMAL NEEDING SUCHTREATMENT COMPRISING ADMINISTERING INTERNALLY TO SAID HOST ANIMAL ANONTOXIC BUT EFFECTIVE QUANTITY OF A COMPOUND OF THE FORMULA:
 2. Amethod according to claim 1 wherein A is hydrogen and B and C arelocated in the meta-, and para-positions.
 3. A method according to claim1 wherein x is
 2. 4. A method according to claim 1 wherein R iscyclohexyl.
 5. A method according to claim 1 wherein A is halogen and Band C are hydrogen.
 6. A method according to claim 1 wherein A ismethoxy and B and C are hydrogen.
 7. A method according to claim 1wherein said compound is N-cyclohexyl-N-cyanoethyl-p-methoxybenzamide.8. A method according to claim 1 wherein said compound isN-cyclohexyl-N-cyanoethyl-m-methoxybenzamide.
 9. A method according toclaim 1 wherein said compound isN-cyclohexyl-N-cyanoethyl-p-chlorobenzamide.
 10. A method according toclaim 1 wherein the quality of said compound administered is betweenabout 0.5 and 10 milligrams per kilogram of the host animal.
 11. Amethod according to claim 1 wherein the quantity of said compoundadministered is between about 1 and 5 milligram per kilogram of the hostanimal.
 12. A method according to claim 1 wherein said compound togetherwith a pharmaceutically acceptable carrier is administered in a unitdose composition in the form of a capsule, tablet, or parenteralformulation.